Sex-related variations in the response of anti-platelet drug therapies targeting
purinergic signaling pathways in sepsis
Sepsis, a complex clinical syndrome resulting from a serious infection, is a major
healthcare problem associated with high morbidity and mortality. Current sepsis
treatments are limited to supportive therapies, and specific pharmacologic treatments
that could greatly improve patient outcomes have not yet been developed With hospital
mortality rates of affected patients reportedly as high as 50%, there is a critical need for
improved methods for treating sepsis. Sex differences in the morbidity and mortality of
sepsis have been observed in various clinical studies and animal models. To date,
females has shown less mortality and decreased organ failure in mice and humans
compared to their male counterpart but the lack of studies comparing both genders
limits our capacity to evaluate the extent of sex-related differences. However, the data
obtained so far suggest that sex should be taken into account when identifying the
optimal pharmacological intervention for sepsis. Our previous studies have shown that
in male mice, anti-platelet therapy that targets the ADP-receptor P2Y12 improves the
outcome of sepsis. However, targeting another platelet ADP-receptor, P2Y1 did not
seem to alter sepsis. Previous data have shown that the
signaling
of
the
P2Y1
and
P2Y12
activation and intracellular
are complex and sex-specific in platelets, however the
data are still unclear. We are lacking similar information in other cells of the immune
system. No studies have investigated sex-related differences in targeting purinergic
signaling during sepsis. Hence this project aims to investigate sex-related differences in
how the purinergic signaling pathways of activated platelets respond to drug therapies
used for treating sepsis. We will use a well-established murine model of sepsis such as
cecal ligation and puncture in male and female P2Y12 knock-out (KO) and P2Y1 KO
mice and compared them with wild-type. We will analyze the outcome of sepsis in
terms of survival, organ dysfunction, plasma cytokine levels, as well as platelet
functions, such as platelet-leukocyte interaction, platelet adhesion markers and platelet
reactivity. The data obtained in this study will provide 1) a more comprehensive
understanding of sex-related differences in platelet behavior during sepsis between
male and female mice, 2) the efficacy and safety of anti-platelet drugs in male and
female.
